Bristol-Myers Squibb and Pfizer Present Investigational Eliquis® (apixaban) Data for Patients with Non-Valvular Atrial Fibrillation (NVAF) Undergoing Cardioversion

PRINCETON, N.J. & NEW YORK–(BUSINESS WIRE)– Bristol-Myers
Squibb Company (NYSE:BMY) and Pfizer
Inc. (NYSE:PFE) today presented findings from EMANATE (Eliquis
evaluated in acute cardioversion coMpared to usuAl treatmeNts
for AnTicoagulation in subjEcts with NVAF), a Phase
4 clinical trial, during a late-breaking hot line presentation at the
ESC Congress 2017, organized by the European Society of Cardiology, in
Barcelona, Spain. This descriptive, randomized, open-label trial
explored the safety and efficacy of apixaban 5 mg twice daily (2.5 mg
lower dose when two of the following were present: age ≥80 years, weight
≤60 kg, or serum creatinine ≥1.5 mg/dL (133μmol/L)) vs. standard of care
(parenteral heparin and/or vitamin K antagonist). The outcomes measured
in this study were the occurrence of acute stroke, systemic embolism,
major bleeding, clinically relevant non-major bleeding and all-cause
death in non-valvular atrial fibrillation patients undergoing
cardioversion. This is an investigational use for Eliquis. Eliquis
is not FDA-approved for the reduction of stroke in NVAF patients
undergoing cardioversion (please see indications and important safety
information for Eliquis later in the press release).

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Cardioversion, which could be achieved pharmacologically, through
electrical shock, or through both means, could quickly restore a heart’s
normal rhythm.¹ A concern related to cardioversion is the
potential for a blood clot in the heart to travel to the brain (stroke)
or other areas (systemic embolism). Guidelines recommend that patients
being considered for cardioversion require at least three weeks of oral
anticoagulation to minimize the potential of cardioversion-related
stroke.^2,3 However, delaying patient intervention could make
it increasingly difficult to achieve and maintain normal heart rhythm.ⁱⁱⁱ
Patients with NVAF may undergo early cardioversion at the discretion of
a cardiologist or emergency room physician to enable the heart to pump
more effectively.

“The EMANATE trial exemplifies the Bristol-Myers Squibb-Pfizer
Alliance’s commitment to expanding understanding of the utility of Eliquis
across broad NVAF patient populations and clinical settings,” said Rory
O’Connor, M.D., Chief Medical Officer, Pfizer Innovative Health. “These
exploratory findings add to the growing body of knowledge for Eliquis in
different NVAF patients, including those at higher-risk.”

This EMANATE study randomized patients with recently diagnosed NVAF who
were anticoagulation-naïve (defined as having received less than 48
hours of anticoagulation) to either apixaban or standard of care
(warfarin with or without heparin). The study protocol encouraged the
use of image guidance according to the guidelines to determine the
absence of a clot in the heart, allowing earlier cardioversion, or
anticoagulation for a minimum of three weeks before cardioversion.
Anticoagulation was administered from randomization until 30 days after
cardioversion. If cardioversion was not performed, anticoagulation was
to be administered for a maximum of 90 days. The apixaban dose was 5 mg
twice daily (or dose reduced per standard criteria). If the imaging
study showed no clot in the heart, five doses of apixaban were
administered to achieve steady-state blood levels before cardioversion.
Alternatively, if no clot was detected, an immediate cardioversion could
be undertaken following a single 10 mg loading dose of apixaban (or dose
reduced per standard criteria) administered at least two hours before
cardioversion, followed by a maintenance regimen. The loading dose
enabled patients to quickly attain steady state-like concentrations of
anticoagulation, allowing for earlier cardioversion.

Results showed that, in the intent-to-treat (ITT) population (n=1500; Eliquis
n=753, heparin/VKA n=747), there were no strokes or systemic emboli in
the Eliquis group compared to six strokes (one hemorrhagic and
five ischemic) and no systemic emboli in the standard of care group. In
the safety analysis population (n=1436; Eliquis n=735,
heparin/VKA n=721), which included all patients receiving one dose of
study drug, there were numerically fewer major bleeding events in the
apixaban treatment group (n=3) than those randomly assigned to standard
of care (n=6), and numerically fewer clinically relevant non-major
bleeding events in the apixaban treatment group (n=11) than those
randomly assigned to standard of care (n=13). It is important to note
that Eliquis increases the risk of bleeding and can cause
serious, potentially fatal, bleeding. There were two deaths in the Eliquis
group (one due to acute alcoholic hepatitis prior to dosing, and one due
to complications related to perforation of the colon) and one in the
standard of care group.

“The current standard of care for reducing the risk of stroke in the
setting of cardioversion is heparin and warfarin, which require
monitoring and potential dose adjustment. This can delay performing
cardioversion,” said Michael D. Ezekowitz, M.B., Ch.B., D.Phil.,
Professor of Medicine in the Sidney Kimmel Medical College at Thomas
Jefferson University, Philadelphia and Lankenau Medical Center and Bryn
Mawr Hospital. “The EMANATE study points to apixaban as a potential
alternative approach. Further research is merited to confirm these
findings.”

“Clinicians often prefer cardioversion earlier after a patient is
diagnosed with non-valvular atrial fibrillation because the sooner the
intervention, the more likely the patient is able to revert back to a
regular heart rhythm,” said Christoph Koenen, M.D., MBA, VP, Development
Lead, Eliquis, Bristol-Myers Squibb. “These exploratory data
offer preliminary insights into the potential effects of Eliquis
in this high-risk clinical setting. Further investigation is needed to
better understand anticoagulation for early cardioversion.”

About Eliquis

Eliquis (apixaban) is an oral selective Factor Xa inhibitor. By
inhibiting Factor Xa, a key blood clotting protein, Eliquis
decreases thrombin generation and blood clot formation. Eliquis is
approved for multiple indications in the U.S. based on efficacy and
safety data from multiple Phase 3 clinical trials. Eliquis is a
prescription medicine indicated to reduce the risk of stroke and
systemic embolism in patients with non-valvular atrial fibrillation
(NVAF); for the prophylaxis of deep vein thrombosis (DVT), which may
lead to pulmonary embolism (PE), in patients who have undergone hip or
knee replacement surgery; for the treatment of DVT and PE; and to reduce
the risk of recurrent DVT and PE, following initial therapy.

ELIQUIS Important Safety Information

CONTRAINDICATIONS

• Active pathological bleeding
• Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic
  reactions)

WARNINGS AND PRECAUTIONS

• Increased Risk of Thrombotic Events after Premature
  Discontinuation: Premature discontinuation of any oral
  anticoagulant, including ELIQUIS, in the absence of adequate
  alternative anticoagulation increases the risk of thrombotic events.
  An increased rate of stroke was observed during the transition from
  ELIQUIS to warfarin in clinical trials in atrial fibrillation
  patients. If ELIQUIS is discontinued for a reason other than
  pathological bleeding or completion of a course of therapy, consider
  coverage with another anticoagulant.
• Bleeding Risk: ELIQUIS increases the risk of bleeding and can
  cause serious, potentially fatal, bleeding.
  • Concomitant use of drugs affecting hemostasis increases the risk
    of bleeding, including aspirin and other antiplatelet agents,
    other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs,
    and NSAIDs.
  • Advise patients of signs and symptoms of blood loss and to report
    them immediately or go to an emergency room. Discontinue ELIQUIS
    in patients with active pathological hemorrhage.
  • There is no established way to reverse the anticoagulant effect of
    apixaban, which can be expected to persist for at least 24 hours
    after the last dose (i.e., about two half-lives). A specific
    antidote for ELIQUIS is not available.
• Spinal/Epidural Anesthesia or Puncture: Patients treated with
  ELIQUIS undergoing spinal/epidural anesthesia or puncture may develop
  an epidural or spinal hematoma which can result in long-term or
  permanent paralysis.

  The risk of these events may be
  increased by the postoperative use of indwelling epidural catheters or
  the concomitant use of medicinal products affecting hemostasis.
  Indwelling epidural or intrathecal catheters should not be removed
  earlier than 24 hours after the last administration of ELIQUIS. The
  next dose of ELIQUIS should not be administered earlier than 5 hours
  after the removal of the catheter. The risk may also be increased by
  traumatic or repeated epidural or spinal puncture. If traumatic
  puncture occurs, delay the administration of ELIQUIS for 48 hours.

  Monitor
  patients frequently and if neurological compromise is noted, urgent
  diagnosis and treatment is necessary. Physicians should consider the
  potential benefit versus the risk of neuraxial intervention in ELIQUIS
  patients.

• Prosthetic Heart Valves: The safety and efficacy of ELIQUIS
  have not been studied in patients with prosthetic heart valves and is
  not recommended in these patients.
• Acute PE in Hemodynamically Unstable Patients or Patients who
  Require Thrombolysis or Pulmonary Embolectomy: Initiation of
  ELIQUIS is not recommended as an alternative to unfractionated heparin
  for the initial treatment of patients with PE who present with
  hemodynamic instability or who may receive thrombolysis or pulmonary
  embolectomy.

ADVERSE REACTIONS

• The most common and most serious adverse reactions reported with
  ELIQUIS were related to bleeding.

TEMPORARY INTERRUPTION FOR SURGERY AND OTHER INTERVENTIONS

• ELIQUIS should be discontinued at least 48 hours prior to elective
  surgery or invasive procedures with a moderate or high risk of
  unacceptable or clinically significant bleeding. ELIQUIS should be
  discontinued at least 24 hours prior to elective surgery or invasive
  procedures with a low risk of bleeding or where the bleeding would be
  noncritical in location and easily controlled. Bridging
  anticoagulation during the 24 to 48 hours after stopping ELIQUIS and
  prior to the intervention is not generally required. ELIQUIS should be
  restarted after the surgical or other procedures as soon as adequate
  hemostasis has been established.

DRUG INTERACTIONS

• Strong Dual Inhibitors of CYP3A4 and P-gp: Inhibitors of
  cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) increase
  exposure to apixaban and increase the risk of bleeding. For patients
  receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose
  of ELIQUIS by 50% when ELIQUIS is coadministered with drugs that are
  strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole,
  itraconazole, ritonavir, or clarithromycin). In patients already
  taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with
  strong dual inhibitors of CYP3A4 and P-gp.
• Strong Dual Inducers of CYP3A4 and P-gp: Avoid concomitant use
  of ELIQUIS with strong dual inducers of CYP3A4 and P-gp (e.g.,
  rifampin, carbamazepine, phenytoin, St. John’s wort) because such
  drugs will decrease exposure to apixaban and increase the risk of
  stroke and other thromboembolic events.
• Anticoagulants and Antiplatelet Agents: Coadministration of
  antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic
  NSAID use increases the risk of bleeding. APPRAISE-2, a
  placebo-controlled clinical trial of apixaban in high-risk post-acute
  coronary syndrome patients treated with aspirin or the combination of
  aspirin and clopidogrel, was terminated early due to a higher rate of
  bleeding with apixaban compared to placebo.

PREGNANCY CATEGORY B

• There are no adequate and well-controlled studies of ELIQUIS in
  pregnant women. Treatment is likely to increase the risk of hemorrhage
  during pregnancy and delivery. ELIQUIS should be used during pregnancy
  only if the potential benefit outweighs the potential risk to the
  mother and fetus.

Please see full U.S. Prescribing Information, including BOXED
WARNINGS and Medication Guide, available at www.bms.com.

Local prescribing information may vary between countries. Please
refer to your local Prescribing Information, including details on
indications, dosage, and safety.

About the Bristol-Myers Squibb/Pfizer Collaboration

In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide
collaboration to develop and commercialize apixaban, an oral
anticoagulant discovered by Bristol-Myers Squibb. This global alliance
combines Bristol-Myers Squibb’s long-standing strengths in
cardiovascular drug development and commercialization with Pfizer’s
global scale and expertise in this field.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission
is to discover, develop and deliver innovative medicines that help
patients prevail over serious diseases. For more information about
Bristol-Myers Squibb, visit us at BMS.com
or follow us on LinkedIn,
Twitter,
YouTube
and Facebook.

About Pfizer Inc.: Working together for a healthier world^®

At Pfizer, we apply science and our global resources to bring therapies
to people that extend and significantly improve their lives. We strive
to set the standard for quality, safety and value in the discovery,
development and manufacture of health care products. Our global
portfolio includes medicines and vaccines as well as many of the world’s
best-known consumer health care products. Every day, Pfizer colleagues
work across developed and emerging markets to advance wellness,
prevention, treatments and cures that challenge the most feared diseases
of our time. Consistent with our responsibility as one of the world’s
premier innovative biopharmaceutical companies, we collaborate with
health care providers, governments and local communities to support and
expand access to reliable, affordable health care around the world. For
more than 150 years, we have worked to make a difference for all who
rely on us. We routinely post information that may be important to
investors on our website at www.pfizer.com.
In addition, to learn more, please visit us on www.pfizer.com
and follow us on Twitter at @Pfizer
and @Pfizer_News,
LinkedIn,
YouTube
and like us on Facebook at Facebook.com/Pfizer.

Bristol-Myers Squibb Forward-Looking Statement

This press release contains « forward-looking statements » as that term
is defined in the Private Securities Litigation Reform Act of 1995
regarding product development. Such forward-looking statements are based
on current expectations and involve inherent risks and uncertainties,
including factors that could delay, divert or change any of them, and
could cause actual outcomes and results to differ materially from
current expectations. No forward-looking statement can be guaranteed.
Forward-looking statements in this press release should be evaluated
together with the many uncertainties that affect Bristol-Myers Squibb’s
business, particularly those identified in the cautionary factors
discussion in Bristol-Myers Squibb’s Annual Report on Form 10-K for the
year ended December 31, 2016, in our Quarterly Reports on Form 10-Q and
our Current Reports on Form 8-K. Bristol-Myers Squibb undertakes no
obligation to publicly update any forward-looking statement, whether as
a result of new information, future events or otherwise.

Pfizer Disclosure Notice

The information contained in this release is as of August 28, 2017.
Pfizer assumes no obligation to update forward-looking statements
contained in this release as the result of new information or future
events or developments.

This release contains forward-looking information about Eliquis
(apixaban), including its potential benefits, that involves substantial
risks and uncertainties that could cause actual results to differ
materially from those expressed or implied by such statements. Risks and
uncertainties include, among other things, the uncertainties inherent in
research and development, including, without limitation, the ability to
meet anticipated clinical trial commencement and completion dates as
well as the possibility of unfavorable clinical trial results, including
unfavorable new clinical data and additional analyses of existing
clinical data; decisions by regulatory authorities regarding labeling
and other matters that could affect the availability or commercial
potential of Eliquis; and competitive developments.

A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended December
31, 2016 and in its subsequent reports on Form 10-Q, including in the
sections thereof captioned “Risk Factors” and “Forward-Looking
Information and Factors That May Affect Future Results”, as well as in
its subsequent reports on Form 8-K, all of which are filed with the SEC
and available at www.sec.gov
and www.pfizer.com.

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